~ 181 ~

The Pharma Innovation Journal 2019; 8(1): 181-197

ISSN (E): 2277- 7695

ISSN (P): 2349-8242

NAAS Rating: 5.03

TPI 2019; 8(1): 181-197

© 2019 TPI

www.thepharmajournal.com

Received: 09-11-2018

Accepted: 14-12-2018

Srilatha Malvey

Talla Padmavathi College of

Pharmacy Kareemabad,

Warangal, Telangana, India

J Venkateshwar Rao

Talla Padmavathi College of

Pharmacy Kareemabad,

Warangal, Telangana, India

Kottai Muthu Arumugam

Annamalai University, FEAT,

Annamalai Nagar,

Chidambaram, Tamil Nadu,

India

Correspondence

Srilatha Malvey

Talla Padmavathi College of

Pharmacy Kareemabad,

Warangal, Telangana, India

Transdermal drug delivery system: A mini review

Srilatha Malvey, J Venkateshwar Rao and Kottai Muthu Arumugam

Abstract In the last two decades, the transdermal drug delivery has become a proven technology that offers vide

range of advantages than conventional route. Because transdermal drug delivery offers controlled as well

as predetermined rate of release of the drug into the patient, and it can easily terminate the drug action,

whenever is required. First-generation transdermal delivery has delivered small, lipophilic, low dose

drugs. Second-generation transdermal delivery has used ultrasound, iontophoresis and chemical

enhancers in delivering the drug. Third-generation transdermal delivery has used microneedles,

electroporation, thermal ablation, microdermabrasion, in delivering the drug. This review emphasizes the

various modules used in delivery of drug with topical application. The main aim of transdermal drug

delivery system is to deliver the drug into systemic circulation with minimal inter and intrasubject

variability.

Keywords: Trandermal delivery, skin, permeation enhancers, evaluation studies

Introduction

Transdermal Drug Delivery Systems

Transdermal drug delivery systems are topically administered medicaments in the form of

patches that deliver the drugs for systemic effects at a predetermined and controlled rate. As it

is one of the most promising methods for drug application. Transdermal delivery of drugs

through the skin to the systemic circulation provides a suitable route of administration for a

variety of clinical indications. Transdermal drug delivery device may be active or passive

design for the delivery of pharmaceuticals through skin barrier here the drug enters the

systemic circulation through diffusion across the skin barrier directly since there is high

concentration of drug in the patch and low concentration in the blood the release occurs for

prolonged time [2].

Transdermal patch uses a special membrane to control the rate at which the liquid drug

enclosed in the reservoir within the patch can pass through the skin and into the bloodstream.

Some drugs must be combined with substances, such as alcohol, that increase their ability to

pierce the skin in order to be used in a skin patch. Drugs administered through skin patches

include scopolamine (for motion sickness), nicotine (for quitting smoking), estrogen (for

menopause and to prevent osteoporosis after menopause), nitro-glycerine (for angina), and

lidocaine to relieve the pain of shingles (herpes zoster).

Transdermal patches were developed in the 1970s and the first was approved by the FDA in

1979 for the treatment of motion sickness. It was a three-day patch that delivered scopolamine.

In 1981, patches for nitro-glycerine were approved, and today there exist a number of patches

for drugs such as clonidine, fentanyl, lidocaine, nicotine, nitro-glycerine, oestradiol,

oxybutinin, scopolamine, and testosterone. There are also combination patches for

contraception, as well as hormone replacement. Depending on the drug, the patches generally

last from one to seven days. The major advantages provided by transdermal drug delivery

include the following: improved bioavailability, more uniform plasma levels, longer duration

of action subsequent reduction in dosing frequency, reduced side effects and improved therapy

due to maintenance of plasma levels up to the end of the dosing interval, compared to a decline

in plasma levels with conventional oral dosage forms. Transdermal patches have been useful in

developing new applications for existing therapeutics and for reducing first-pass drug-

degradation effects. Patches can also reduce side effects; for example, oestradiol patches are

used by more than a million patients annually. Aroma patches, weight loss patches, and no

medicated patch markets include thermal and cold patches, nutrient patches, skin care patches3

(a category that consists patches that measure sunlight exposure).

~ 182 ~

The Pharma Innovation Journal

Advantages of transdermal patches [5].

Topical patches are apainless, non-invasive way to

deliver substances directly into the blood.

Topical patches can bypass first-pass hepatic metabolism

Termination of medicament can be possible by removing

the patch from skin.

Drug which is, stomach irritant can modify to topical

delivery.

Topical patches have fewer side effects than oral

medications.

Topical patches are easier to use and remember.

Topical patches are cost-effective.

Topical patch can release the drug at steady state over the

long period of time.

Topical patch can bypass the enzymes action on it.

Limitation [5].

TDDS cannot deliver ionic drugs.

TDDS cannot achieve high drug levels in blood/plasma.

It cannot develop for drugs of large molecular size.

TDDS cannot deliver drugs in a pulsatile fashion.

TDDS cannot develop if drug or formulation causes

irritation to skin.

Limitation of TDDS can be overcome to some extent by

novel approaches such as Iontophoresis, electroporation

and ultrasound.

Adjustment of dose is required in order to achieve

therapeutic concentration.

Adverse events

In 2005, the FDA announced that they were investigating

reports of death and other serious adverse events related to

narcotic overdose in patients using Duragesic, the fentanyl

transdermal patch for pain control. The Duragesic product

label was subsequently updated to add safety information in

June 2005. In 2008, two manufacturers of the Fentanyl patch,

Alza Pharmaceuticals (a division of major medical

manufacturer Johnson & Johnson) and Sandoz, subsequently

issued a recall of their versions of the patch due to a

manufacturing defect that allowed the gel containing the

medication to leak out of its pouch too quickly, which could

result in overdose and death. As of 2010, Sandoz no longer

uses gel in its transdermal fentanyl patch; instead, Sandoz-

branded fentanyl patches use a matrix/adhesive suspension

(where the medication is blended with the adhesive instead of

held in a separate pouch with a porous membrane) [9].

Anatomy of the Skin [12].

Skin anatomy

The epidermis is the outer layer, serving as the physical and

chemical barrier between the interior body and exterior

environment; the dermis is the deeper layer providing the

structural support of the skin, below which is a loose

connective tissue layer, the hypodermis which is an important

depot of fat.

Epidermis

The epidermis is stratified squamous epithelium. The main

cells of the epidermis are the keratinocytes, which synthesis

the protein keratin. Protein bridges called desmosomes

connect the keratinocytes, which are in a constant state of

transition from the deeper layers to the superficial. The four

separate layers of the epidermis are formed by the differing

stages of keratin maturation. The epidermis varies in

thickness from 0.05 mm on the eyelids to 0.8±1.5 mm on the

soles of the feet and palms of the hand. Moving from the

lower layers upwards to the surface, the four layers of the

epidermis are:

1) Stratum basale (basal or germinativum cell layer)

2) Stratum spinosum (spinous or prickle cell layer)

3) Stratum granulosum (granular cell layer)

4) Stratum corneum (horny layer).

In addition, the stratum lucidum is a thin layer of translucent

cells seen in thick epidermis. It represents a transition from

the stratum granulosum and stratum corneum and is not

usually seen in thin epidermis. Together, the stratum

spinosum and stratum granulosum are sometimes referred to

as the Malpighian layer.

Stratum Basale

The innermost layer of the epidermis which lies adjacent to

the dermis comprises mainly dividing and non-dividing

keratinocytes, which are attached to the basement membrane

by hemi desmosomes. As keratinocytes divide and

differentiate, they move from this deeper layer to the surface.

Making up a small proportion of the basal cell population is

the pigment (melanin) producing melanocytes. These cells are

characterized by dendritic processes, which stretch between

relatively large numbers of neighboring keratinocytes.

Melanin accumulates in melanosomes that are transferred to

the adjacent keratinocytes where they remain as granules.

Melanin pigment provides protection against ultraviolet

radiation; chronic exposure to light increases the ratio of

melanocytes to keratinocytes, so more are found in facial skin

associated to the lower back and a greater number on the

outer arm compared to the inner arm. The number of

melanocytes is the same in equivalent body sites in white and

black skin but the distribution and rate of production of

melanin is different. Intrinsic ageing diminishes the

melanocyte population. Merkel cells are also found in the

basal layer with large numbers in touch sensitive sites such as

the fingertips and lips. They are closely associated with

cutaneous nerves and seem to be involved in light touch

sensation.

Stratum spinosum

As basal cells reproduce and mature, they move towards the

outer layer of skin, initially forming the stratum spinosum.

Intercellular bridges, the desmosomes, which appear as

‘prickles’ at a microscopic level, connect the cells.

Langerhans cells are dendritic, immunologically active cells

derived from the bone marrow, and are found on all epidermal

surfaces but are mainly located in the middle of this layer.

They play a important role in immune reactions of the skin,

acting as antigen-presenting cells.

Stratum granulosum

Continuing their transition to the surface the cells continue to

fatten, lose their nuclei and their cytoplasm appears granular

at this level.

Stratum corneum

The final outcome of keratinocyte maturation is found in the

stratum corneum, which is made up of layers of hexagonal-

shaped, non-viable cornified cells known as corneocytes. In

most areas of the skin, there are 10±30 layers of stacked

corneocytes with the palms and soles having the most. Each

corneocytes is surrounded by a protein envelope and is filled

~ 183 ~

The Pharma Innovation Journal

with water-retaining keratin proteins. The cellular shape and

orientation of the keratin proteins add strength to the stratum

corneum. Surrounding the cells in the extracellular space are

stacked layers of lipid bilayers (The resulting structure

provides the natural physical and water-retaining barrier of

the skin. The corneocytes layer can absorb three times its

weight in water but if its water content drops below 10% it no

longer remains pliable and cracks. The movement of

epidermal cells to this layer usually takes about 28 days and is

known as the epidermal transit time.

Fig 1: Cross section of skin

Dermis

The dermis varies in thickness, ranging from 0.6 mm on the

eyelids to 3 mm on the back, palms and soles. It is found

below the epidermis and is composed of atough, supportive

cell matrix. Two layers comprise the dermis:

A thin papillary layer

A thicker reticular layer.

The papillary dermis lies below and connects with the

epidermis. It contains thin loosely arranged collagen fibers.

Thicker bundles of collagen run parallel to the skin surface in

the deeper reticular layer, which extends from the base of the

papillary layer to the sub cutis tissue. The dermis is made up

of fibroblasts, which produce collagen, elastin and structural

proteoglycans, together with immune competent mast cells

and macrophages. Collagen fibers make up 70% of the

dermis, giving it strength and toughness. Elastin maintains

normal elasticity while proteoglycans provide viscosity and

hydration. Rooted Aroma dermatology within the fibrous

tissue of the dermis are the dermal vasculature, lymphatics,

nervous cells and fibers, sweat glands, hair roots and small

quantities of striated muscle.

Hypodermis

The hypodermis is the adipose tissue layer which is found in

between of dermis and aponeurosis and fasciae of the

muscles. The subcutaneous adipose tissue is structurally and

functionally being well integrated with the dermis through the

nerve and vascular networks. The hypodermis layer is

composed of loose connective tissues and its, thickness varies

according to the surface of body.

Drug penetration pathways [15].

There are critically three ways in which a drug molecule can

cross the intact stratum corneum through the intercellular lipid

domains; or by a transcellular route. A particular drug is

likely to permeate by a combination of these routes, with the

relative contributions of these pathways to the gross flux

governed by the physicochemical properties of the molecule.

The appendgeal route

Skin appendages offer a continuous channel directly across

the stratum corneum barrier. However, their influence on drug

penetration is hindered by number of factors. The surface

areaoccupied by hair follicles and sweat ducts are small

(typically 0.1% of skin’s surface area), therefore limiting the

area available for direct contact of the applied drug

formulation.

Transcellular route/ Intracellular route

Drugs entering the skin via the transcellular route pass

through corneocytes. Corneocytes containing highly hydrate

keratin provide an aqueous environment from which

hydrophilic drugs can pass. The diffusion pathway for a drug

via the transcellular route requires a number of partitioning

and diffusion steps.

Intercellular route

The intercellular pathway involves drug diffusing through the

continuous lipid matrix. This route is a significant obstacle for

two reasons:

Recalling the ‘bricks and mortar’ model of the stratum

corneum, the inter digitating nature of the corneocytes yields

a tortuous pathway for intercellular drug permeation, which is

in contrast to the relatively direct path of the transcellular

route.

The intercellular domain is a region of alternating structured

bilayered consequently, a drug must sequentially partition into

and diffuse through repeated aqueous and lipid domains. This

route is generally accepted as most common path for small

uncharged molecules penetrating the skin.

~ 184 ~

The Pharma Innovation Journal

Fig 2: Routes of drug permeation

Physicochemical properties of penetrant [16]

Partition coefficient

For molecules with intermediate partition coefficient (log P 1

to 3) and for highly lipophilic molecules (log P>3), the

intercellular route will be almost the pathway used to traverse

the stratum corneum. However, for these molecules a further

consideration is the ability to partition out of the stratum

corneum into the aqueous viable epidermal tissues. For more

hydrophilic molecules (log P<1), the transcellular route

probably predominates.

Molecular size

A second major factor in determining the flux of a material

through human skin is the size of the molecule. However, for

simplicity the molecular weight is generally taken as an

approximation of molecular size. It has been suggested that an

inverse relationship existed between transdermal flux and

molecular weight of the molecule.

Solubility/melting point

It is well known that most organic materials with high melting

points have relatively low aqueous solubility at normal

temperature and pressure. The lipophilic molecules tend to

permeate through the skin faster than more hydrophilic

molecules. However, while lipophilicity is a desired property

of transdermal candidates, it is also necessary for the

molecule to exhibit some aqueous solubility since topical

medicaments are generally applied from an aqueous

formulation.

Ionization

According to pH-partition hypothesis, only the unionized

forms of the drug canpermeate through the lipid barrier in

significant amounts.

Penetrant concentration

Assuming membrane related transport, increasing

concentration of dissolved drug causes a proportional increase

in flux. At concentration higher than the solubility, excess

solid drug functions as a reservoir and helps maintain a

constant drug constitution for a prolonged period of time.

Diffusion coefficient

Penetration of drug depends on diffusion coefficient of drug.

At a constant temperature the diffusion coefficient of drug

depends on properties of drug, diffusion medium and

interaction between them.

Other factors

Beyond the factors mentioned above, there are other

molecular properties that can affect drug delivery through the

skin. Drug binding is a factor that should be born in mind

when selecting appropriate candidates. Interactions between

drug substances and the tissue can vary from hydrogen

bonding to weak Van der Waals forces and the effect of drug

binding on flux across the tissue will vary depending on the

permeant, e.g. with a poorly water soluble drug in an aqueous

donor solution, significant binding to the stratum corneum

may completely retard drug flux. Consequently, there will be

a delay between applying a drug to the surface of the tissue

and its appearance in a receptor solution (in vitro) or the

blood (in vivo). Depending on the type of formulation

selected, other factors may be important in a transdermal

delivery system. For example, if the drug is suspended then

the particle size may become a main regulator of flux.

Physicochemical properties of the drug delivery system

Release characteristics

Solubility of the drug in the vehicle determines the release

~ 185 ~

The Pharma Innovation Journal

rate. The mechanism of drug release depends on the following

factors:

Whether the drug molecules are dissolved or suspended

in the delivery systems.

The interfacial partition coefficient of the drug from the

delivery system to the skin tissue.

pH of the vehicle.

Composition of the drug delivery systems

The composition of the drug delivery systems, e.g. boundary

layers, thickness, polymers, vehicles not only affects the rate

of drug release, but also the permeability of the stratum

corneum by means of hydration, making with skin lipids, or

other sorption promoting effects.

Enhancement of Transdermal permeation

Majority of drugs will not penetrate skin at rates sufficiently

high for therapeutic efficacy. In order to allow clinically

useful transdermal permeation of most drugs, the penetration

can be improved by the addition of a permeation promoter

into the drug delivery systems.

Physiological factors

Skin barrier properties in the neonate and young infant

The skin of newborns is known to be relatively susceptible to

irritants, other variables related to stratum corneum function

such as pH and stratum corneum hydration may enhance the

irritant potential to newborn skin. Skin surface pH values in

newborns are significantly higher in all body sites than those

in adult skin, but stabilize at values similar to adults within

the first month. There are also significant changes in the

metabolic capacity of infants, whether full or preterm and

adult levels of cutaneous enzyme activity are not observed

until 2 months or even 6-12 months of age which may

additionally account for the sensitivity of baby skin to

irritants. The skin surface of the newborn is slightly

hydrophobic and relatively dry and rough when compared to

that of older infants. Stratum corneum hydration stabilizes by

the age of 3 months.

Skin barrier properties in aged skin

There are changes in the physiology of aged skin (>65 years).

The corneocytes are shown to increase in surface area which

may have implications for stratum corneum function due to

the resulting decreased volume of intercorneocyte space per

unit volume of stratum corneum. The moisture content of

human skin decreases with age. There is a flattening of the

dermoepidermal junction and, consequently, the area

available for diffusion into the dermis is diminished.

Race

Racial differences between black and white skins have been

shown in some anatomical and physiological functions of the

skin although data is relatively sparse. In black skin, increased

intracellular cohesion, higher lipid content and higher

electrical skin resistance levels compared to whites have been

demonstrated.

Body site

It is readily apparent that skin structure varies to some degree

over the human body. However, the relative permeability of

different skin sites is not simply a function of stratum

corneum thickness as different permeants exhibit varied rank

orders through different skin sites. It is apparent that genital

tissue usually provides the most permeable site for

transdermal drug delivery. The skin of the head and neck is

also relatively permeable compared to other sites of the body

such as the arms and legs.

Skin temperature

The human body maintains a temperature gradient across the

skin from around 37 ºC to around 32 ºC at the outer surface.

Since diffusion through the stratum corneum is a passive

process, elevation of the skin temperature can induce

structural alterations within the stratum corneum, and these

modifications can also increase diffusion through the tissue.

Skin condition

Acids and alkalis, many solvents like chloroform, methanol

damage the skin cells and promote penetration. Diseased state

of patient alters the skin conditions. The intact skin is better

barrier but the above mentioned conditions affect penetration.

Blood supply

Changes in peripheral circulation can affect transdermal

absorption.

Skin metabolism

Skin metabolizes steroids, hormones, chemical carcinogens

and some drugs. Soskin metabolism determines efficacy of

drug permeated through the skin.

Basic components of TDDS [16]

Polymer matrix/ Drug reservoir

Drug

Permeation enhancers

Pressure sensitive adhesive (PSA)

Backing laminates

Rate controlling membrane

Release liner

Other excipients like plasticizers and solvents

Polymer matrix

Polymers are the backbone of a transdermal drug delivery

system. Systems for transdermal delivery are fabricated as

multilayered polymeric laminates in which a drug reservoir or

a drug polymer matrix is sandwiched between two polymeric

layers: an outer impervious backing layer that prevents the

loss of drug through the backing surface and an inner

polymeric layer that functions as an adhesive and/or rate

controlling membrane. Polymer selection and design must be

considered when striving to meet the diverse criteria for the

fabrication of effective transdermal drug delivery systems.

The main challenge is in the design of a polymer matrix,

followed by optimization of the drug loaded matrix not only

in terms of release properties, but also with respect to its

adhesion-cohesion balance, physicochemical properties,

compatibility and stability with other components of the

system as well as with skin.

The polymers utilized for TDDS can be classified as:

Natural polymers

cellulose derivatives, zein, gelatin, shellac, waxes, gums,

natural rubber, chitosan, starch, etc.

Synthetic elastomers

polybutadiene, polyisobutylene, silicon rubber, nitrile,

acrylonitrile, styrene-butadiene rubber, neoprene, butylrubber,

polysiloxane, etc.

~ 186 ~

The Pharma Innovation Journal

Synthetic polymers

polyvinyl alcohol, polyvinylchloride, polyethylene,

polypropylene, polyacrylate, polyamide, polyurea,

polyvinylpyrrolidone, epoxy polymethylmethacrylate, ethyl

cellulose, hydroxy propyl cellulose etc.

The polymers like cross linked polyethylene glycol, eudragits,

ethyl cellulose and hydroxyl propyl methylcellulose are used

as matrix formers for TDDS. Other polymers like EVA (Ethyl

vinyl acetate), silicon rubber and polyurethane are used as rate

controlling membrane.

Drug

The most important criteria for TDDS are that the drug should

possess the right Physicochemical and pharmacokinetic

properties. The selection of drug for transdermal drug

delivery depends upon various factors.

Physicochemical properties

The drug should have some degree of solubility in both oil

and water (Ideally greater than 1 mg/ml). The substance

should have melting point less than 200°F. Concentration

gradient across the membrane is directly proportional to the

log solubility of drug in the lipid phase of membrane, which

in turn is directly proportional to the reciprocal of melting

point. Substances having a molecular weight of less than 600

units are suitable. A saturated aqueous solution of the drug

should have a pH value between 5 to 9 and drugs highly

acidic or alkaline in solution are not suitable for TDDS;

because they get ionized rapidly at Physiological pH.

Biological properties

The drug should have short biological half-life.

Drug should be very potent, i.e., it should be effective in

few mgs per day (Ideally less than 25 mg/day).

Therapeutic index should be low.

The drug should be non-irritant and non-allergic to

human skin.

The drug should be stable when in contact with the skin.

The drug should not stimulate an immune reaction to the

skin.

Tolerance to drug must not develop under near zero order

release profile of transdermal delivery.

The drug should not get irreversibly bound in the

subcutaneous tissue.

The drug should not get extensively metabolized in the

skin.

Drugs, which degrade in the GIT or are inactivated by

hepatic first-pass effect, are suitable candidates for

transdermal delivery.

Drugs, which have to administer for a long period of time

or which cause adverse effects to non-target tissues can

also be formulated for transdermal delivery.

Permeation enhancers

Substances exist which temporarily diminish the

impermeability of the skin are known as accelerants or

sorption promoters or penetration enhancers. These include

water, pyrrolidone, fatty acids and alcohols, azone and its

derivatives, alcohols and glycols, essential oils, terpenes and

derivatives, sulfoxides like dimethylsulfoximide (DMSO) and

their derivatives, urea and surfactants.

Surfactants

These are proposed to enhance polar pathway transport

especially of hydrophilic drugs. The ability of a surfactant to

alter penetration enhancing of a drug.

Anionic surfactants Sodium lauryl sulphate, Decodecylmethylsulphoxide, DMSO

etc.

Nonionic surfactants Pluronic F 127, Pluronic F68 etc.

Enhancer actions can be classified by lipid-protein

partitioning concept. This hypothesis suggests that enhancers

act by one or more ways selected from three main

possibilities.

Lipid action Some enhancers interact with the organized intracellular lipid

structure of the stratum corneum so as to disrupt it and make

it more permeable to drug molecules. Some solvents act by

extracting the lipid components and thus make the horny layer

more permeable.

Protein modification

Ionic surface active molecules in particular tend to interact

well with the keratin in the corneocytes, to open up the dense

keratin structure and make it more permeable. The

intracellular route is not usually prominent in drug

permeation, although drastic reductions to this route could

open up an alternative path for drug penetration.

Partitioning promotion

Many solvents can enter the stratum corneum, change its

solvent properties and thus increase the partitioning of a

second molecule into the horny layer. This molecule may be a

drug, a co enhancer or a co-solvent. e.g. Ethanol has been

used to increase the penetration of the drug molecules

nitroglycerin and estradiol.

Pressure sensitive adhesive (PSA)

A PSA is a material that helps in maintaining an intimate

contact between transdermal system and the skin surface PSA

is a material that adheres with no more than applied finger

pressure, is aggressively and permanently tacky, exerts a

strong holding force and should be removable from a smooth

surface without leaving a residue. Adhesion involves a liquid-

like flow resulting in wetting of the skin surface upon the

application of pressure and when pressure is removed, the

adhesive sets in that state. Acrylic-poly isobutylene- and

silicone-based adhesives are used mostly in the design of

transdermal patches. The selection of an adhesive is based on

a number of factors, including the patch design and drug

formulation. For reservoir systems with a peripheral adhesive,

an incidental contact between the adhesive and the drug or

penetration enhancers must not cause instability of the drug,

penetration enhancer, or the adhesive. In the case of reservoir

systems that include a face adhesive, the diffusing drug must

not affect the adhesive. For matrix designs in which the

adhesive, the drug and the penetration enhancers must be

compounded, the selection will be more complex. The

physicochemical characteristics of a drug adhesive

combination- such as solubility and partition coefficient and

adhesive characteristics such as the extent of crosslinking will

determine the choice of adhesive for a drug. When

formulating a PSA, a balance of four properties must be taken

into account: tack, peel adhesion, skin adhesion and cohesive

strength.

~ 187 ~

The Pharma Innovation Journal

Backing layer

It protects the patch from the outer environment. The backing

layer should be impermeable to drug and penetration

enhancers. It does a function of holding the entire system and

protects drug reservoir from atmosphere. The commonly used

backing materials are polyesters, aluminized polyethylene

terephthalate and siliconized polyethylene terephthalate.

Rate controlling membrane

Reservoir-type transdermal drug delivery systems contain an

inert membrane enclosing an active agent that diffuses

through the membrane at a finite controllable rate. The release

rate controlling membrane can be nonporous so that the drug

is released by diffusing directly through the material or the

material may contain fluid-filled microspores, in which case

the drug may additionally diffuse through the fluid, thus

filling the pores. In the case of nonporous membranes, the rate

of passage of drug molecules depends on the solubility of the

drug in the membrane and the membrane thickness. Hence,

the choice of membrane material must conform to the type of

drug being used. By varying the composition and thickness of

the membrane, the dosage rate per area of the device can be

controlled.

Release liner

During storage the patch is covered by a protective liner that

is removed and discharged immediately before the application

of the patch to skin. It is therefore regarded as a part of the

primary packaging material rather than apart of dosage form

for delivering the drug. However, as the liner is in intimate

contact with the delivery system, it should comply with

specific requirements regarding chemical inertness and

permeation to the drug, penetration enhancer and water.

Typically, release liner is composed of a base layer which

may be non-occlusive or occlusive and a release coating layer

made up of silicon or Teflon. Other materials used for TDDS

release liner include polyester foil and metalized laminates.

Plasticizer and solvents

Plasticizer

In transdermal systems, plasticizers are used to improve the

brittleness of the polymer and to provide flexibility. They are

generally non-volatile organic liquids or solids with low

melting temperature and when added to polymers, they cause

changes in definite physical and mechanical characteristics of

the material. Upon addition of plasticizer, flexibilities of

polymer macromolecules or macromolecular segments

increase as a result of loosening of tightness of intermolecular

forces. Many of polymers used in pharmaceutical

formulations are brittle and require the addition of plasticizer

into the formulation. The plasticizers with lower molecular

weight have more molecules per unit weight compared to the

plasticizers with higher molecular weight. These molecules

can more easily penetrate between the polymer chains of the

film forming agent and can interact with the specific

functional groups of the polymer. By adding plasticizer to a

polymeric material, elongation at break, toughness and

flexibility are expected to increase; on the other hand, tensile

stress, hardness, electrostatic chargeability, and glass

transition temperature (Tg) are expected to decrease.

Solvents

Various solvents are used to solve or disperse the polymer and

adhesive or drug used in preparation of transdermal system.

Among those chloroform, methanol, acetone, iso propanol

and dichloromethane are used frequently.

Reservoir

Microreservoir

~ 188 ~

The Pharma Innovation Journal

Adhesive dispersion

Matrix diffusion/ dispersion

Fig 3: Different types of TDDS

Types of Transdermal Patch [34]

Single-layer Drug -in-Adhesive

The adhesive layer of this system also contains the drug. In

this type of patch, the adhesive layer not only serves to adhere

the various layers together, along with the entire system to the

skin, but is also responsible for the releasing of the drug. The

adhesive layer is surrounded by a temporary liner and a

backing.

Multi-layer Drug-in-Adhesive The multi-layer drug-in adhesive patch is similar to the

single-layer system in that both adhesive layers are also

responsible for the releasing of the drug. The multi-layer

system is different however that it adds another layer of drug-

in -adhesive, usually separated by a membrane (but not in all

cases). This patch also has a temporary liner-layer and a

permanent backing.

Reservoir

Unlike the Single-layer and Multi-Layer Drug, inadhesive

systems the reservoir transdermal system has a separate drug

layer. The drug layer is a liquid compartment containing a

drug solution or suspension separated by the adhesive layer.

This patch is also backed by the backing layer. In this type of

system, the rate of release is zero order.

Matrix

The Matrix system has a drug layer of a semisolid matrix

containing a drug solution or suspension. The adhesive layer

in this patch surrounds the drug layer partially overlaying it.

Vapour Patch

In this type of patch, the adhesive layer not only serves to

adhere the various layers together but also to release vapor.

The vapor patches are new on the market and they release

essential oils for up to 6 hours. The vaporspatches release

essential oil sand is used in cases of decongestion mainly.

Other vapor patches on the market are controller vapor

patches that improve the quality of sleep. Vapour patches that

reduce the quantity of cigarettes that one smokes in a month

are also available on the market.

Care taken while applying Transdermal patch 1. The part of the skin where the patch is to be applied

should be properly cleaned.

2. Patch should not be cut because cutting the patch

destroys the drug delivery system.

3. Before applying a new patch it should be made sure that

the old patch is removed from the site.

4. Care should be taken while applying or removing the

patch because anyone handling the patch can absorb the

drug fromthe patch.

5. The patch should be applied accurately to the site of

administration.

Permeation enhancement techniques [16]:

The method employed for modifying the barrier properties of

the stratum corneum to enhance drug permeation and

absorption through skin may be classified into the fallowing

categories

1. Chemical enhancement techniques

~ 189 ~

The Pharma Innovation Journal

2. Physical enhancement techniques

3. Vesicular carriers

4. Miscellanous techniques

5. Carriers/vehicles

Chemical enhancement techniques

The use of Chemical permeation enhancers (CPEs) over the

other techniques has certain advantages, including design

flexibility of the patch and ease of patch application over a

large area (>10 cm2). An ideal penetration enhancer should

reversibly reduce the barrier resistance of the Stratum

corneum without damaging the skin cells.

Ideal penetration enhancers should possess the following

properties:

Pharmacologically inert Nontoxic, non-irritating, and

non-allergenic

Rapid onset of action; predictable and suitable duration

of action for the drug used

Reversible effect of the CPE on the barrier property of

SC.

Chemically and physically compatible with the delivery

system.

Readily incorporated into the delivery system

Inexpensive and cosmetically acceptable

Because the skin provides such a tough barrier to the delivery

of most drugs, a broad range of changed chemical additives

have been tested to increase transdermal penetration during

the last two decades. Much of the cited literature is found in

patents as well as pharmaceutical science literature. Even

though many chemical entities have been recognized, only a

few were introduced in the market due to several limitations,

which include their economic feasibility and the toxic effects

on skin, which make them undesirable for developing

transdermal patches.

Mechanism of chemical penetration enhancement

Penetration enhancers may act by one or more of three main

mechanisms

1. Disruption of the highly ordered structure of stratum

corneum lipid.

2. Interaction with intercellular protein.

3. Improved partition of the drug, co enhancer or solvent

into the stratum corneum.

The enhancer act by altering one of three pathways. The key

to altering the polar pathway is to cause protein

conformational change or solvent swelling. The fatty acid

enhancers increased the fluidity of the lipid protein portion of

the stratum corneum. Some enhancers act on both polar and

non-polarpathways by altering the multi laminate pathway for

penetration. Enhancers can increase the drug diffusivity

through skin proteins. The type of enhancer employed has a

significant impact on the design and development.

dm/dt = DC0K/h

If we plot the cumulative mass of diffusant, m, passing per

unit area through the membrane, at long time the graph

approaches linearity and its, slope its yield the steady flux,

where Co is the constant concentration of drug in donor

solution, K is the partition coefficient of the solute between

the membrane and the bathing solution, D is the diffusion

coefficient and h is thickness of membrane. From the above

equation, we deduce the ideal properties of a molecule that

would penetrating stratum corneum well. These are:

Low molecular mass, preferably less than 600Daltons.

Adequate solubility in oil and water so that membrane

concentration gradient may be high.

Sulphoxides and similar chemicals

Dimethyl sulphoxides (DMSO) is one of the earliest and most

widely studied penetration enhancers. It is a powerful solvent

which hydrogen bonds with itself rather than with water. It is

colourless, odourless and is hydroscopic and is often used in

many areas of pharmaceutical sciences as a “universal

solvent”. DMSO alone has been applied topically to treat

systemic inflammation. DMSO works rapidly as a penetration

enhancer - spillage of the material onto the skin can be tasted

in the mouth within a second. Although DMSO is an excellent

accelerant, it does create problems. The effect of the enhancer

is concentration-dependent and generally cosolvents

containing > 60% DMSO are needed for optimum

enhancement efficacy. However, at these relative high

concentrations, DMSO can cause erythema of the stratum

corneum. Denaturing of some skin proteins results in

erythema, scaling, contact uticaria, stinging and burning

sensation. Since DMSO is problematic for use as a

penetration enhancer, researchers have investigated a similar

chemically-related material as a accelerant.

Dimethylacetamide (DMAC) and dimethylformamide (DMF)

are similarly powerful solvents. However, Southwell and

Barry, showing a 12-fold increase in the flux of caffeine

permeating across a DMF-treated human skin, concluded that

the enhancer caused irreversible membrane damage. DMF

irreversibly damages human skin membranes but has been

found in vivo to promote the bioavailability of betamethasone-

17-benzoate as measured by vasoconstrictor assay. DMSO

may also extract lipids, making the horny layer more

permeable by forming aqueous channels. It has been

postulated that DMSO denatures the intercellular structural

proteins of the stratum corneum, or promotes lipid fluidity by

disruption of the ordered structure of the lipid chains. In

addition, DMSO may alter the physical structure of the skin

by elution of lipid, lipoprotein and nucleoprotein structures of

the stratum corneum. Decylmethylsulfoxide (DCMS) is

thought to promote permeation enhancement as a result of

protein-DCMS interaction creating aqueous channels, in

addition to lipid interactions.

Alkanes

Long chain alkanes (C7-C16) have been shown to enhance

skin permeability by non-destructive alteration of the stratum

corneum barrier.

Azone

Azone (1-dodecylazacycloheptan-2-one or laurocapran) was

the first molecule specifically designed as a skin penetration

enhancer. Azone is a colourless, odourless liquid with a

melting point of -7 ºC and it possesses a smooth, oily but yet

non-greasy feel. Azone is a highly lipophilic material with a

log p octanol / water of around 6.2 and it is soluble in and

compatible with most organic solvents including alcohol and

propylene glycol. Azone enhances the skin transport of a wide

variety of drugs including steroids, antibiotics and antiviral

agents. Azone is most effective at low concentrations, being

employed typically between 0.1-5 % but more often between

1-3%. Azone partitions into a bilayer lipid to disrupt their

~ 190 ~

The Pharma Innovation Journal

packing arrangement but integration into the lipid is unlikely

to be homogeneous. Azone aggravates dynamic structural

disorder of the intercellular lamellar lipid structure all through

the stratum corneum and the design of fluid domains

containing the intercellular lipids, which was recommended

by 2H NMR assay. Another mechanism was also projected

based on the alteration of the lateral bonding within stratum

corneum lipid lamellae. Azone increase penetration through

the stratum corneum by affecting both the hydrophilic and

lipophilic routes of penetration. Azone increases the fluidity

of the lipid layer.

Pyrrolidones

Pyrrolidones have been used as permeation enhancers for

numerous molecules including hydrophilic (e.g. mannitol and

5-flurouracil) and lipophilic (progesterone and

hydrocortisone) permeants. N-methyl-2- pyrolidone was

employed with limited success as a penetration enhancer for

captopril when formulated in a matrix-type transdermal patch.

The pyrrolidones partition well into human stratum corneum

within the tissue and they may act by altering the solvent

nature of the membrane. Pyrrolidones have been used to

generate reservoirs within the skin membrane. Such a

reservoir effect offers a potential for sustained release of a

permeant from the stratum corneum over extended time

periods.

Urea Urea promotes transdermal permeation by facilitating

hydration of the stratum corneum and by the formation of

hydrophilic diffusion channels within the barrier. As urea

itself possesses only borderline penetration enhancing

activity, attempts have been made to synthesis analogues

containing more potent enhancing moieties.

Fatty acids and Esters Percutaneous drug absorption has been increased by a wide

variety of fatty acids and their esters, the most popular of

which is oleic acid. A general trend has been seen that

unsaturated fatty acids are more effective in enhancing

percutaneous absorption of drugs than their saturated

counterparts. It is of interest to note that many penetration

enhancers such as azone contain saturated or unsaturated

hydrocarbon chains and some structure-activity relationships

have been drawn from the extensive studies of Aungst who

employed a range of fatty acids, acids, alcohols, sulphoxides,

surfactants and amides as enhancers for naloxone. Shin, et, al.

studied various penetration enhancers like glycols (diethylene

glycol and tetraethylene glycol), fatty acids (lauric acid,

myristic acid and capric acid) and non-ionic surfactant

(polyoxyethylene-2-oleyl ether, polyoxy ethylene-2-stearly

ether) on the release of triprolidone. Lauric acid in Propylene

glycol enhanced the delivery of highly lipophilic antiestrogen.

Oleic acid greatly increased the flux of many drugs such as

increasing the flux of salicylic acid 28-fold and 5-flurouracil

flux 56-fold through human skin membrane in vitro. The

enhancer interacts with and modifies the lipid domains of the

stratum corneum as would be expected for a long chain fatty

acid with cis- configuration.

Alcohols, fatty alcohols and glycols

Alcohols may stimulus transdermal penetration by a number

of mechanisms. The alkyl chain length of the alkanols (fatty

alcohols) is an important parameter in the promotion of

permeation enhancement. Augmentation appears to increase

as the number of carbon units increases, up to a limiting

value. In addition, lower molecular weight alkanols are

thought to act as solvents, enhancing the solubility of drugs in

the matrix of the stratum corneum. Disruption of the stratum

corneum integrity through extraction of biochemicals by the

more hydrophobic alcohols almost certainly also contributes

to enhanced mass transfer through this tissue. Ethanol is the

most commonly used alcohol as a transdermal penetration

enhancer. Ethanol acts as a penetration enhancer by extracting

large amounts of stratum corneum lipids. It also increases the

number of free sulphydryl groups of keratin in the stratum

corneum proteins. Usually, pretreatment of skin with ethanol

increases the permeation of hydrophilic compounds, while it

decreases that of hydrophobic ones. The molecular

complexity of different glycol molecules is a determinant of

their efficacy as permeation enhancers. Solubility of the drug

in the delivery vehicle is markedly influenced by the number

of ethylene oxide functional groups on the enhancer molecule;

this solubility modification may either enhance or retard

transdermal flux depending on the specific drug and delivery

environment. The activity of propylene glycol (PG) is thought

to result from solvation of α keratin within the stratum

corneum; the occupation of proteinaceous hydrogen bonding

sites reducing drug-tissue binding and thus promoting

permeation. PG is widely used as a vehicle for penetration

enhancers and shows synergistic action when used with, for

example, oleic acid.

Surfactants Many surfactants are capable of interacting with the stratum

corneum to increase the absorption of drugs and other active

compounds from products applied to the skin. Skin

penetration measurements are valuable in quantifying these

effects and observing the influence of surfactant chemistry

and concentration. A surfactant interacts with skin by

depositing onto the stratum corneum, thereby disorganizing

its structure. Then surfactant can solubilise or remove lipids

or water-soluble constituents in or on the surface of the

stratum corneum. Finally, it can be transported into and

through the stratum corneum. This last effect is related to the

surfactant and stratum corneum protein interaction and

epidermal keratin denaturation. In general, anionic surfactants

are more effective than cationic and non-ionic surfactants in

enhancing skin penetration of target molecules. Some anionic

surfactants interact strongly with both keratin and lipids,

whereas the cationic surfactants interact with the keratin

fibrils of the cornified cells and result in a disrupted cell-lipid

matrix. Non-ionic surfactants enhance absorption by inducing

fluidization of the stratum corneum lipids. Scheuplein and

Ross reported that the capacity of the statum corneum to

retain significant quantities of membrane-bound water is

reduced in the presence of sodium dodecanoate and sodium

dodecyl sulfate. This effect is readily reversible upon removal

of the agents. These investigations proposed that anionic

surfactants alter the permeability of the skin by acting on the

helical filaments of the stratum corneum, thereby resulting in

the uncoiling and extension of keratin filaments to produce

keratin. Then they cause an expansion of the membrane,

which increases permeability. However, more recent findings

suggest that impairment of the skin’s barrier properties is

unlikely to result from changes in protein conformation alone.

Based on differential scanning calorimetry results, sodium

lauryl sulfate (SLS) disrupted both the lipid and the protein

components. The amount of surfactant that penetrates the skin

~ 191 ~

The Pharma Innovation Journal

after the disruption of the skin barrier depends on the

monomer activity and the critical micelle concentration

(CMC). Above the CMC, the added surfactant exists as

micelles in the solution and micelles are too large to penetrate

the skin. The extent of barrier disruption and penetration

enhancement of a surfactant is also strongly dependent on

surfactant structure, especially alkyl chain length. In general,

studies have shown that surfactants having 12 carbons in their

alkyl chain cause more disruption to the skin barrier and allow

drugs to penetrate more readily than those that have more or

less than 12 carbons. The explanation for this optimum of 12

carbons is not known yet.

Essential oil, terpenes and terpenoids

Terpenes are found in essential oils, and are compounds

comprising of only carbon, hydrogen and oxygen atoms, but

which are not aromatic. Numerous terpenes have long been

used as medicines as well as flavoring and fragrance agents.

The essential oils of eucalyptus, chenopodium. ylang-ylang

has been found to be effective penetration enhancers for 5-

flouorouracil traversing human skin in vivo.

Cornwell et al. investigated the effect of 12 sesquiterpenes on

the permeation of 5-flurouracil in human skin. Pretreatment of

epidermal membranes with sesquiterpene oil or using solid

sesquiterpenes saturated in dimethyl isosorbide increased the

absorption of 5- flurouracil.

L-menthol has been used to facilitate in vitro permeation of

morphine hydrochloride through hairless rat skin as well as

diffusion of imipramine hydrochloride across rat skin and

hydrocortisone through hairless mouse skin. One mechanism

by which this agent operates is to modify the solvent nature of

the stratum corneum, thus improving drug partitioning into

the tissue. Many terpenes permeate human skin well and large

amounts of terpene have been found in the epidermis after

application from a matrix-type patch. Terpenes may also

modify drug diffusivity through the membrane. During steady

state permeation experiments using terpenes as penetration

enhancers, the lag time for permeation was usually reduced,

indicating some increase in drug diffusivity through the

membrane following terpene treatment.

Cyclodextrins

Cyclodextrins are biocompatible substances that can form

inclusion complexes with lipophilic drugs with a resultant

increase in their solubility, particularly in aqueous solutions.

However, cyclodextrins alone were determined be to less

effective as penetration enhancers than when combined with

fatty acids and propylene glycol.

Oxazolidinones

Oxazolidinones are a new class of chemical agents which

have the potential for use in many cosmetic and personal care

product formulations. This is due to their ability to localize

co-administered drug in skin layers, resulting in low systemic

permeation. The structural features of these permeation

enhancers are closely related to sphingosine and ceramide

lipids which are naturally found in the upper skin layers.

Oxazolidinones such as 4-decyloxazolidin-2-one has been

reported to localize the delivery of many active ingredients

such as retinoic acid and diclofenac sodium in skin layers.

This compound has a higher molecular weight and

lipophilicity than other solvent-type enhancers, physical

characteristics that may be beneficial in terms of a reduction

in local toxicity because of the lack of effective absorption of

these enhancers into the lower skin layers where irritation is

likely to be occur.

Physical enhancement techniques

The various classes of active systems under development

includes Iontophoresis, Electrophoresis, Micro needles,

needle less injection, stretching, ultrasound, magnetophoresis,

radio frequency, lasers, photomechanical waves and

temperature manipulation. Some most commonly employed

techniques include the fallowing.

Iontophoresis

Iontophoresis passes a few milli amperes of current to a few

square centimeters of skin through the electrode placed in

contact with the formulation, which facilitates drug delivery

across the barrier. Mainly used of pilocarpine delivery to

induce sweating as part of cystic fibrosis diagnostic test.

Iontophoretic delivery of lidocaine appears to be a promising

approach for rapid onset of anesthesia.

Fig 4: Iontophoresis

Electroporation

Electroporation ismethod of application of short, high-voltage

electrical pulses to the skin. After electroporation, the

permeability of the skin for diffusion of drugs is increased by

4 orders of magnitude. The electrical pulses are believed to

form transient aqueous pores in the stratum corneum, through

which drug transport occurs. It is safe and the electrical pulses

can be administered painlessly using closely spaced

electrodes to constrain the electric field within the nerve-free

stratum corneum.

Fig 5: Electroporation

~ 192 ~

The Pharma Innovation Journal

Application by ultrasound

Application of ultrasound, particularly low frequency

ultrasound, has been shown to enhance transdermal transport

of various drugs including macromolecules. It is also known

as sonophoresis. Katz et al., reported on the use of low-

frequency sonophoresis for topical delivery of EMLA cream.

Fig 6: Ultra sound

Use of microscopic projection

Transdermal patches with microscopic projections called

microneedles were used to facilitate transdermal drug

transport. Needles ranging from approximately 10-100 µm in

length are arranged in arrays. When pressed into the skin, the

arrays make microscopic punctures that are large enough to

deliver macromolecules, but small enough that the patient

does not feel the penetration or pain. The drug is surface

coated on the microneedles to aid in rapid absorption. They

are used in development of cutaneous vaccines for tetanus and

influenza. Various other methods are also used for the

application of the transdermal patches like thermal poration,

magnetophoresis, and photomechanical waves. However,

these methods are in their early stage of development and

required further detail studying.

Fig 7: Micro needles

Vesicular carriers

Liposomes and other vesicles

Liposomes are colloidal particles moulded as concentric

bimolecular layers that are capable of encapsulating drugs.

Liposomes acts by penetrating the epidermis, carrying the

drug into skin and those large multilamellar vesicles could

lose their external bilayer during penetration and these

liposome lipids penetrate into the stratum corneum by

adhering onto the surface of the skin and, successively

destabilizing, and fusing or mixing with the lipid matrix.

Thereafter, they may act as penetration enhancers, loosening

the lipid structure of the stratum corneum and promoting

reduced barrier function of these layers to the drug, with less

well-packed intercellular lipid structure forms, and with

subsequent increased skin partitioning of the drug. Studies

have focused on delivery of agents via liposomes like anti-

psoriatic agent via ethanolic liposomes, caffeine for

hyperproliferative diseases,

Niosomes

Niosomes are vesicles composed of non-ionic surfactants that

have been evaluated as carriers for a number of drug and

cosmetic applications. In fact, if compared with conventional

liposomes (phospholipids) niosomes (non-ionic surfactant

vesicles) offer higher chemical stability, lower costs, and

great availability of surfactant classes. Niosomes seems an

interesting drug delivery system in the treatment of

dermatological disorders. In fact, topically applied niosomes

can increase the residence time of drugs in the stratum

corneum and epidermis, while reducing the systemic

absorption of the drug. They are thought to improve the horny

layer properties; both by reducing trans epidermal water loss

and by increasing smoothness viarefilling lost skin lipids.

Transfersomes

These are vesicles composed of phospholipids as their main

ingredient with 10-25% surfactant and 3-10% ethanol.

Liposomes are too large to pass through pores of less than

50nm in size; transfersomes up to 500nm can squeeze to

penetrate the stratum corneum barrier spontaneously. The

driving force for penetration into the skin is the “Transdermal

gradient” caused by the difference in water content between

the restively dehydrated skin surface (approximately 20%

water) and the aqueous viable epidermis. Studies have been

focused on delivery of agents like vaccines, retinyl palmitate,

estradiol, copper, zinc, superoxide dismutase, insulin. In some

cases, the transferosomes drug delivery with some physical

enhancement method iontophoresis for estradiol and

microneedles for docetaxel.

Miscellenous techniques

Selection of correct drug or prodrug

Drug should be selected in such a way that it fits in the

criteria of transdermal delivery. The prodrug approach has

been investigated to enhance dermal and transdermal delivery

of drugs with unfavourable partition coefficients. The prodrug

design strategy generally involves addition of a promoiety to

increase partition coefficient and hence solubility and

transport of the parent drug in the stratum corneum. Upon

reaching the viable epidermis, esterases release the parent

drug by hydrolysis thereby optimizing solubility in the

aqueous epidermis. The intrinsic poor permeability of the

very polar 6- mercaptopurine was increased up to 240 times

using S-6- acyloxymethyl and 9- dialkylaminomethyl

promoieties.

Chemical potential adjustment

The maximum skin penetration rate is obtained when a drug is

at its highest thermodynamic activity as is the case in a

supersaturated solution. The diffusion of paraben from

saturated solutions in eleven different solvents through a

silicone membrane was determined. Due to the different

solubility of the parabens in the various solvents, the

concentration varied over two orders of magnitude. However,

paraben flux was the same from all solvents, as the

~ 193 ~

The Pharma Innovation Journal

thermodynamic activity remained constant because saturated

conditions were maintained throughout the experiment.

Supersaturated solutions can occur due to evaporation of

solvent or by mixing of cosolvents. Clinically, the most

common mechanism is evaporation of solvent from the warm

skin surface, which probably occurs, in many topically

applied formulations. In addition, if water is imbibed from the

skin into the vehicle and acts as an anti-solvent, the

thermodynamic activity of the permeant would increase.

Ion pairs and complex coacervates

Charged drug molecules do not readily partition into or

permeate through human skin. Formation of lipophilic ion

pairs has been investigated to increase stratum corneum

penetration of charged species. This strategy involves adding

an oppositely charged species to the charged drug, forming an

ion-pair in which the charges are neutralised so that the

complex can partition into and permeate through the stratum

corneum. The ion-pair then dissociates in the aqueous viable

epidermis releasing the parent charged drug, which can

diffuse within the epidermal and dermal tissues.

Eutectic systems The melting points of a drug influences solubility and hence

skin penetration. According to regular solution theory, the

lower the melting point, the greater the solubility of a material

in a given solvent, including skin lipids. The melting point of

a drug delivery system can be lowered by formation of a

eutectic mixture, a mixture of two components which, at a

certain ratio, inhibit the crystalline process of each other, such

that the melting point of the two components in the mixture is

less than that of each component alone. A number of eutectic

systems containing a penetration enhancer as the second

components have been reported, for example: Ibuprofen with

terpenes, and methyl nicotinate, propranolol with fatty acids,

and lignocaine with menthol.

Vehicles/carriers

Micro or nanocapsules

These are composed of multiple concentric bilayers of

surfactant; separated by a polar liquid medium, generally in

water in which the hydrophilic additives can be in corporate.

Their lipid core allows encapsulation of lipid additives and

their multi-lamellar (lipid/water) structure creates good skin

affinity leading to cutaneous penetration and good hydration.

Nano emulsions/submicron emulsion (SME’S)/Mini

emulsions

These are oil in water emulsions with an average droplet size

ranging from 100 to 500nm. They have very good stability

and they do not undergo phase separation during storage.

They have a liquid lipophilic core and are appropriate for

lipophilic compound separation.

Solid lipid nano particles (SLN’s)

These droplets are made by solid lipids. Their sizes range

from 500-1000nm. They can be stabilized by surfactants or

polymers. There are mainly 3 structures: Homogenous matrix,

drug enriched shell, and drug enriched core. They can protect

active components against chemical degradation and

modulate compound release. SLN’S also possess occlusive

properties because of formation of a film on the skin. The film

formed by lipid fusion is supposed to be a pore-less film with

improved skin hydration and protection properties.

Multiple emulsions

These W/O/W emulsions consist in the dispersion of a W/O

emulsion in an aqueous phase under several conditions. One

can incorporate water-soluble ingredients and oil soluble

additives. They substances can be protected and released

sustained by controlling droplet breakdown. These systems

can have high oily phase.

Micro emulsions

These formulations have been shown to be superior for

cutaneous delivery compared to other conventional vehicles.

These systems are identified as transparent mixtures of water,

oil and surfactants. They are thermodynamically stable and

optically isotropic. Micro emulsions are spontaneously

produced in a narrow range of oil-water-surfactant

composition, represented on pseudo-ternary diagram phases.

These are dynamic systems with transdermal delivery

properties could be attributed to their excellent solubilising

properties. Their high solubilising properties improve bio

dispensability and thus reduce the efficient dose thereby

increasing tolerability. Furthermore, they have an ability to

restructure the skin and hair make micro emulsion

formulations adapt to altered skin and hair conditions.

Transdermal work done

Y. Madhusudhan Rao et al., Developed Carvedilol

Trandermal patches and evaluated for Physico-chemical, ex-

vivo mechanical properties using different ratios of HPMC,

HPC, ERS 100, and 8% v/w d-limonene as penetration

enhancer and 20% v/w dibutyl phthalate as plasticizer and the

results are found that the formulation containing HPMC

E15cps: ERL 100 in 4:1 ratio showed maximum drug release

in 24hrs.

Ramesh Gannu et al., Developed Matrix type Transdermal

Drug Delivery System of Nitrendipine using blends of HPMC

E 15cps and Eudragit RL 100 in different ratios using 6%

Carvone as penetration enhancer and 15% propylene glycol as

plasticizer and found that the patches consisting of Eudragit

RL-100 and HPMC E15cps in the ratios of 2:3 and 1:4

showed maximum drug release.

M. Aqil et al., Formulated matrix type drug delivery systems

of Pinacidil Monohydrate by film casting method on mercury

substrate and evaluated in vitro prior to this work, the TDDS

was composed of polymers Eudragit RL 100, and PVP K-30

in different ratios along with 20% w/w of Drug; Pinacidil

monohydrate, 5% w/w of plasticizer, polyethylene glycol-

400, and 5% w/w of penetration enhancers, dimethyl

sulfoxide. The films were evaluated in vivo for drug

permeation. The results indicate that increasing the quantity

of ERL100 upto 60% w/w leads to an increment in the rate

and extent of drug absorbed and extent of drug absorbed and

higher % reduction in blood pressure.

Evaluation of transdermal patches [27].

Physicochemical evaluation

In vitro evaluation

In vivo evaluation

1. Physicochemical Evaluation [18]:

Thickness The thickness of Transdermal film is determined by travelling

microscope, dial gauge, screw gauge or micrometre at

different points of the film. The average reading is calculated

~ 194 ~

The Pharma Innovation Journal

Uniformity of weight

Weight variation is studied by individually weighing 10

randomly selected patches and calculating the average weight.

The individual weight should not deviate significantly from

the average weight.

Drug content determination

An accurately weighed portion of film (about 100 mg) is

dissolved in 100 mL of suitable solvent in which drug is

soluble and then the solution is shaken continuously for 24 hrs

in shaker incubator. Then the whole solution is sonicated.

After sonication and subsequent filtration, drug in solution is

estimated spectrophotometrically by appropriate dilution.

Concentration of drug is calculated by using standard graph.

Content uniformity test

10 patches are selected and content is determined for

individual patches. If 9 out of 10 patches have content

between 85% to 115% of the specified value and one has

content not less than 75% to 125% of the specified value, then

transdermal patches pass the test of content uniformity. But if

3 patches have content in the range of 75% to 125%, then

additional 20 patches are tested for drug content. If these 20

patches have range from 85% to 115%, then the transdermal

patches pass the test.

Moisture content

The prepared films are weighed individually and kept in a

desiccators containing calcium chloride at room temperature

for 24hrs. The films are weighed again after a specified

interval until they show a constant weight. The percent

moisture content is calculated using following formula.

Moisture Uptake Weighed films are kept in a desiccator at room temperature

for 24 h. These are then taken out and exposed to 84%

relative humidity using saturated solution of Potassium

chloride in a desiccator until a constant weight is achieved. %

moisture uptake is calculated as given below.

Flatness

A transdermal patch should possess a smooth surface and

should not constrict with time. This can be demonstrated with

flatness study. For flatness determination, one strip is cut

from the centre and two from each side of patches. The length

of each strip is measured and variation in length is measured

by determining percent constriction. Zero percent constriction

is equivalent to 100 percent flatness.

% constriction = I1 – I2 X 100

I2 = Final length of each strip

I1 = Initial length of each strip

Folding Endurance Evaluation of folding endurance involves determining the

folding capacity of the films subjected to frequent extreme

conditions of folding. Folding endurance is determined by

repeatedly folding the film at the same place until it break.

The number of times the films could be folded at the same

place without breaking is folding endurance value.

Tensile Strength

To determine tensile strength, polymeric films are sandwiched

separately by corked linear iron plates. One end of the films is

kept fixed with the help of an iron screen and other end is

connected to a freely movable thread over a pulley. The

weights are added gradually to the pan attached with the

hanging end of the thread. A pointer on the thread is used to

measure the elongation of the film. The weight just sufficient

to break the film is noted. The tensile strength can be

calculated using the following equation.

Tensile strength= F/a.b (1+L/l)

F is the force required to break; a is width of film;

b is thickness of film; L is length of film;

l is elongation of film at break point.

Tack properties

It is the ability of the polymer to adhere to substrate with little

contact pressure. Tack is dependent on molecular weight and

composition of polymer as well as on the use of tackifying

resins in polymer.

Thumb tack test

The force required to remove thumb from adhesive is a

measure of tack.

Rolling ball test

This test involves measurement of the distance that stainless

steel ball travels along an upward facing adhesive. The less

tacky the adhesive, the further the ball will travel.

Quick stick (Peel tack) test

The peel once required breaking the bond between an

adhesive and substrate is measured by pulling the tape away

from the substrate at 90 at the speed of 12 inch/min.

Probe tack test

Force required to pull a probe away from an adhesive at a

fixed rate is recorded as tack.

In vitro release studies [27]

The paddle over disc

(USP apparatus 5) This method is identical to the USP paddle

dissolution apparatus, except that the transdermal system is

attached to a disc or cell resting at the bottom of the vessel

which contains medium at 32 ±5°C.

The Cylinder modified USP Basket

(USP apparatus 6). This method is similar to the USP basket

type dissolution apparatus, except that the system is attached

to the surface of a hollow cylinder immersed in medium at 32

±5°C.

The reciprocating disc

(USP apparatus 7) In this method patches attached to holders

are oscillated in small volumes of medium, allowing the

apparatus to be useful for systems delivering low

concentration of drug. In addition, paddle over extraction cell

method may be used.

In vitro permeation studies The amount of drug available for absorption to the systemic

pool is greatly dependent on drug released from the polymeric

transdermal films. The drug reached at skin surface is then

passed to the dermal microcirculation by penetration through

~ 195 ~

The Pharma Innovation Journal

cells of epidermis, between the cells of epidermis through

skin appendages. Usually permeation studies are performed

by placing the fabricated transdermal patch with rat skin or

synthetic membrane in between receptor and donor

compartment in a vertical diffusion cell such as Franz

diffusion cell or keshary-chien (KC) diffusion cell. The

transdermal system is applied to the hydrophilic side of the

membrane and then mounted in the diffusion cell with

lipophilic side in contact with receptor fluid. The receiver

compartment is maintained at specific temperature (usually

32±5°C for skin) and is continuously stirred at a constant rate.

The samples are withdrawn at different time intervals and

equal amount of buffer is replaced each time. The samples are

diluted appropriately and absorbance is determined

spectrophotometric ally. Then the amount of drug permeated

per centimetre square at each time interval is calculated.

Design of system, patch size, surface area of skin, thickness

of skin and temperature etc. are some variables that may

affect the release of drug. So permeation study involves

preparation of skin, mounting of skin on permeation cell,

setting of experimental conditions like temperature, stirring,

sink conditions, withdrawing samples at different time

intervals, sample analysis and calculation of flux i.e., drug

permeated per cm2 per sec.

Horizontal-type skin permeation system This has been widely used for the evaluation of drug

permeation across skin. The cell is divided in receptor and

donor compartments with a low solution volume (3.5ml) for

each compartment and a small membrane area (0.64cm2).

They are continuously stirred by matched set of star-head

magnets, which are rotated at a speed of 600 rpm. The system

is controlled by thermostatic water through a water jacket

surrounding the two compartments.

Franz diffusion cell [29]

The cell is composed of two compartments: donor and

receptor. The receptor compartment has a volume of 12 ml

and effective surface area of 4.90 cm2. The diffusion buffer is

continuously stirred at 600rpm by a magnetic bar. The

temperature in the bulk of the solution is maintained by

circulating thermostated water through a water jacket that

surrounds the receptor compartment.

Flow-through diffusion cell

Flow through diffusion cells have the advantage that they can

be used when the drug has lower solubility in the receptor

compartment. This cell can be fully automated and connected

directly to HPLC. They have large capacity donor chamber to

allow appropriate loading of the applied compound and a low

volume (0.3ml) receiving chamber that ensures rapid removal

of penetrant at relatively low pumping rates.

In vivo Studies

In vivo evaluations are the true depiction of the drug

performance. The variables which cannot be taken into

account during in vitro studies can be fully explored during in

vivo studies. in vivo evaluation of TDDS can be carried out

using animal models human volunteers.

Animal models

Considerable time and resources are required to carry out

human studies, so animal studies are preferred at small scale.

The most common animal species used for evaluating

transdermal drug delivery system are mouse, hairless rat,

hairless dog, hairless rhesus monkey, rabbit, guinea pig etc.

Various experiments conducted lead us to a conclusion that

hairless animals are preferred over hairy animals in both in

vitro and in vivo experiments. Rhesus monkey is one of the

most reliable models for in vivo evaluation of Transdermal

drug delivery in man.

Human models The final stage of the development of a transdermal device

involves collection of pharmacokinetic and pharmacodynamic

data following application of the patch to human volunteers.

Clinical trials have been conducted to assess the efficacy, risk

involved, side effects, patient compliance etc. Phase I clinical

trials are conducted to determine mainly safety in volunteers

and phase II clinical trials determine short term safety and

mainly effectiveness in patients. Phase III trials indicate the

safety and effectiveness in large number of patient population

and phase IV trials at post marketing surveillance are done for

marketed patches to detect adverse drug reactions. Though

human studies require considerable resources but they are the

best to assess the performance of the drug.

Table 1: List of marketed Transdermal products

Product name Drug Manufacturer Indication

Transderm scope Scopolamine Alza/Novartis Motion sickness

Transderm nitro Nitro glycerine Alza/Novartis Angina pectoris

Vivelle Estradiol Noven pharmaceuticals Post menstrual syndrome

Duragesic Clonidine Alza/janseen pharmaceuticals Moderate severe pain

Habitraol Nicotine Novartis Smoking cessation

Androderm Testoterone Theratech/glaxosmithkline Hypogonadism in males

NuvelleTS Estrogen, progesterone Ethical holdings, schering Harmone replacement

Catapress-TTS Clonidine Alza/Boehinger ingelheim Hypertension

Butrans Buprenorphine Mundi pharma Opiod analgesic

Emsam Selegiline Bristol myre’s squibb Parkinson’s disease

Daytrana Methyl phenidate Noven pharmaceuticals Attention deficit hyper activity disorder

Exelon Rivastigmine Novartis Dementia associated with parkinson’s disease

Lidoderm Lidocaine Grunenthal Pain associated with post herpetic neuralgia

Tolubuterol Hokumalin Abbott japan Bronchial asthama

Ortro evra Estradiol Orthro-Mencil Phrmctls Birth control

Prostep Nicotine Elan corp smoking cessation

Deponit Nitro glycerine Schwarz pharma Angina pectoris

Combipatch Estradiol Noven Inc/ Aventis Harmone replacement therapy

~ 196 ~

The Pharma Innovation Journal

Conclusion

The transdermal drug delivery system (TDDS) has great

potential for delivery of the drug on both hydrophilic and

hydrophobic. It has been designed as an alternative safety and

very feasible route for systemic drug delivery with permeation

enhancers (physical, chemical) transdermal route is suitable

for the patients, who are bedridden unconscious. Many new

researchers are going on in present day to incorporate newer

drug via this system which enhances modular drug delivery,

novel carriers’ systems: microemlusion, nanoemlusion,

liposomes, ethosomes, niosome can also be incorporated into

the transdermal patch, which shows the important of

formulation for better therapeutics action with prolonged

effect. Transdermal drug delivery system is an alternative and

promising way to systemic administration of drugs with and

without permeation enhancers. The present article is to give

information about the research work done so far, structure of

skin, permeation enhancers (Physical and chemical)

techniques of delivery and evaluation studies.

Acknowledgement

The Author is thankful to guide for this continuous support in

developing this article.

Conflict of interest: There is no conflict of interest

References

1. Chein Yie W. Trandermal Therapeutic systems,

Controlled Drug Delivery: Fundamentals & Applications,

Robinson Joseph R, Lee Vincent HL. Eds, New York:

Marcel Dekker, 1987, 523.

2. Bhardwaj S, Sharma PK, Vipin KG, Nitin K, Mayank B.

Recent advancement in transdermal drug delivery system,

International Journal of Pharma Professional’s Research.

2011; 2(1):24-35.

3. Divyesh P, Nirav P, Meghal P, Navpreet K, Transdermal

drug delivery system: Review International Journal of

Biopharmaceutical and Toxicology Research. 2011;

1(1):61-80.

4. Chein Yie W. In Transdermal Drug Delivery & Delivery

Systems, Novel drug Delivery Systems. Eds, New York:

Marcel Dekker, 1992, 301-302.

5. Vyas SP, Khar. Control Drug Delivery Concepts and

Advances, Vallabh P, 2002, 411-447.

6. Allen LV, Popovich NG, Ansel HC. Ancel’s

Parmaceutical Dosage Forms and Drug Delivery

Systems, 8th Edition, Lippincott Williams & Wilkins,

2005, 298-315.

7. Bary B. Transdermal Drug delivery; Aulton M E, The

science of dosage from design, Churchill Livingston,

2002, 499-533.

8. Cleary GW. Transdermal controlled release systems,

Medical applications of controlled release. 2005; 1:203-

251.

9. Vyas SP, Khar RK. Controlled drug delivery: concepts

and advances, vallabh P, 1st edition, 2002, 411-447.

10. Tortora G, Grabowski S. Principles and anatomy and

physiology, John Wiley and sons Inc., 9th edition, 2001,

150-153.

11. Wilson KJW, Waugh A. Eds, Ross and Wilson: Anatomy

and physiology in health and illness, 8th edition, Churchill

Livingftone, 1996, 360-366.

12. Matt V, Waterman J, Ian M, Basic physiology of the

skin, Basic science, Elsevier. 2010, 469-472.

13. Baary BW. Dermatological formulations: Percutaneous

absorption, Drugs and pharmaceutical sciences. Marcel

Dekker INC, 1983; 18:1-39.

14. Chien Yie W. In Transdermal Drug Delivery & Delivery

Systems, Novel drug Delivery Systems. Eds, New York:

Marcel Dekker, 1992, 301.

15. Gaur PK, Mishra S, Purohit S, Dave K. Transdermal drug

delivery system: A Review, Asian Journal of

Pharmaceutical and Clincal Research. 2009; 2(1):14-20.

16. Vinay V, Pooja M, Navneet S, Surender V. Various

penetration enhancement techniques in transdermal drug

delivery, International Journal of Pharmacy and

Technology. 2011; 3(2):2373-2401.

17. Hiren JP, Darshan G, Dushyant B. Penetratration

enhancers for transdermal drug delivery system: A

Review. IJPI’s Journal of Pharmaceutics and

Cosmetology. 2011; 1(2).

18. Mark RP, Robert L. Transdermal drug delivery, Nat

Biotechnol, 2008, 1261-1268.

19. Brain W, Barry. Is transdermal drug delivery research

still important today?, DDT. 2001; 6(19):967-971.

20. Ashok K, Nikhila P, Lakshmana SP, Gopal P.

Transdermal drug delivery system: An Overview.

International Journal of Pharmaceutical Sciences Review

and Research. 2010; 3(2):49-54.

21. Mamatha T, Venkateswara RJ, Mukkanti K, Ramesh G.

Development of matrix type transdermal patches of

lercanidipine hydrochloride; Physicochemical and in vivo

characterisation, DARU. 2010; 18(1):45-54.

22. Mamatha T, Venkateswara RJ, Mukkanti K, Ramesh G.

Transdermal Drug Delivery System for Atomoxetine

Hydrochloride-In vitro and Ex vivo Evaluation. Current

Trends in Biotechnology and Pharmacy. 2009; 3(2):15-

23.

23. Nirit RMD. Will the evolution of overactive bladder

delivery systems increase patient compliance? Reviews in

Urology. 2009; 11(2):45-51.

24. Scott A, Mac D. The evolution of transdermal/topical

overactive bladder therapy and its benefits over oral

therapy, Reviews in Urology. 2009; 1:48-76.

25. Vinay P, Aisha K, Shyamala B, Vasiha B. Forulation and

Evaluation of toltirodine tartarate transdermal films for

the treatment of Overactive Bladder. Int. J.Pharm. Tech.

Res. 2009; 3:799-804.

26. Anil JS. Development and Characterization Of

transdermal therapeutic systems of tramadol

hydrochloride. Asian Journal of Pharmaceutics. 2008,

265-269.

27. Mandal SC. In vitro release and permeation kinetics of

pentazocine from matrix-dispersion type transdermal

drug delivery systems, Drug Development and industrial

Pharmacy. 1994; 20(11):1933-1941.

28. Murthy TEGK, Kishore VS. Effect of casting solvent and

polymer on permeability of propranolol hydrochloride

through membrane controlled transdermal drug delivery

system, Indian Journal of Pharmaceutical Sciences. 2007;

69(5):646-650.

29. Ramesh G, Vamshi YV, Kishan V, Rao YM.

Development of Nitrendipine Transdermal Patches: In

vitro and Ex vivo Characterization. Current drug Del.

2007; 4:69-76.

30. Aqil M, Ali A, Yasmin S, Kiran D, Abul KN, Kollapa

KP. In vivo Characterization of Monolithic Matrix Type

Transdermal Drug Delivery Systems of pinacidil

~ 197 ~

The Pharma Innovation Journal

Monohydrate: A Technical Note. AAPS Pharm Sci Tech.

2006; 7(1).

31. Gattani SG, Gaud RS, Chaturvedi S C. Formulation and

Evaluation of Transdermal films of Ondansetron

Hydrochloride, Indian Drugs. 2006; 43(3):245-250.

32. Mutalik S, Udupa N. Formulation development, in vitro

and in vivo evaluation of membrane controlled

transdermal systems of glipizide. J Pharm. Pharmaceut

Sci. 2005; 8:26-38.

33. Jain AK, Thomas NS, Panchagnula R. Transdermal drug

delivery of imipramine hydrochloride. I. Effect of

terpenes. J Cont. Rel. 2002; 79:93-101.

34. Mandal S, Bhattacharya M, Sarod KG. In vitro release

and permeatiom kinetics of Pentazocine from Matriz-

dispersion type transdermal drug delivery system, Drug

Development and industrial pharmacy. 1994;

20(11):1993-1941. www.fda.gov.

35. Wade A, Weller PJ. Hand book of pharmaceutical

excipients. Washinton, DC: American Pharmaceutical

Publishing assoc, 2000, 252-255 & 401-406.